Multiflora and Gram-Negative Microorganisms Predominate in Infections Affecting Pelvic Endoprostheses Following Tumor Resection.
Periprosthetic infections after pelvic reconstruction are common, with reported rates ranging from 11% to 53%. Management of these infections is troublesome, as they commonly necessitate multiple surgical interventions and implant removal. The epidemiology and outcomes of these infections are largely unknown. The aim of this study was to analyze the causative microorganisms and the clinical outcome of treatment in a series of patients with pelvic endoprostheses affected by infection following tumor resection. In this retrospective, multicenter cohort study, we identified all patients who developed an infection after endoprosthetic reconstruction in periacetabular tumor resection, between 2003 and 2017. The microorganisms that were isolated during the first debridement were recorded, as were the number of reoperations for ongoing infection, the antimicrobial treatment strategy, and the outcome of treatment. In a series of 70 patients who underwent pelvic endoprosthetic reconstruction, 18 (26%) developed an infection. The type of pelvic resection according to the Enneking-Dunham classification was type P2-3 in 14 (78%) of these patients and type P2 in 4 (22%). Median follow-up was 66 months. Fourteen (78%) of the 18 patients with infection had a polymicrobial infection. Enterobacteriaceae were identified on culture for 12 (67%). Of a total 42 times that a microorganism was isolated, the identified pathogen was gram-negative in 26 instances (62%). Microorganisms associated with intestinal flora were identified 32 times (76%). At the time of latest follow-up, 9 (50%) of the patients had the original implant in situ. Of these, 2 had a fistula and another 2 were receiving suppressive antibiotic therapy. In the remaining 9 (50%) of the patients, the original implant had been removed. At the time of final follow-up, 3 of these had a second implant in situ. The remaining 6 patients had undergone no secondary reconstruction. Infections that affect pelvic endoprostheses are predominantly polymicrobial and caused by gram-negative microorganisms, and may be associated with intestinal flora. This differs fundamentally from mono-bacterial gram-positive causes of conventional periprosthetic joint infections and may indicate a different pathogenesis. Our results suggest that prophylaxis and empiric treatment may need to be re-evaluated. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Working alongside next of kin to enhance discharge: A quality improvement collaboration to co-design discharge for mental health patients.
Mental health (MH) patients seen in the emergency department (ED) setting are often viewed in isolation, outside of the context of their loved ones, the next of kin (NOK). This is especially problematic when a patient is detained under the mental health act. This project aimed to improve this engagement. A sense of urgency was created from a guiding coalition of the local MH and ED executive of a rural hospital. The vision was communicated to the team for action. This was then institutionally incorporated as best practice during a 3 month trial. NOK were engaged more frequently as a result of this quality improvement strategy, rising to 90.8% (2021) from 63.2% (2020) compared to the previous year χ2 (1, N=166) =18.75, p = .000015. Admissions for all MH patients from the emergency department fell to 28.3% (2021) from 39% (2020) χ2 (1, N=652) =8.32, p = .0039. Working with NOK is a best practice strategy that was embraced by clinicians when highlighted. This resulted in less restrictive practice and more community treatment. Creating a frame for the patient that is standardised, provides containment and co-designs future health care is beneficial.


Old World cutaneous leishmaniasis challenges in Morocco, Algeria, Tunisia and Iran (MATI): a collaborative attempt to combat the disease.
Cutaneous leishmaniasis (CL) is a main public health problem in Morocco, Algeria, Tunisia and Iran, known as the MATI region. During the biennial meeting of Pasteur Institutes of the MATI region in November 2016 in Tehran, a Leishmania panel formed of scientists with different expertise in CL research from the MATI and Institut Pasteur in Paris, proposed a new consortium to develop an integrative research approach to better understand this disease. The proposed consortium synergizes three complementary thematics on Leishmania genetics, host immune response, and vector transmission. Moreover, assessing the social impact of CL with the aim to raise awareness at both the national and international levels will be a major focus of this consortium.


Inter-muscular coherence and functional coordination in the human upper extremity after stroke.
Muscle coordination and motor function of stroke patients are weakened by stroke-related motor impairments. Our earlier studies have determined alterations in inter-muscular coordination patterns (muscle synergies). However, the functional connectivity of these synergistically paired or unpaired muscles is still unclear in stroke patients. The goal of this study is to quantify the alterations of inter-muscular coherence (IMC) among upper extremity muscles that have been shown to be synergistically or non-synergistically activated in stroke survivors. In a three-dimensional isometric force matching task, surface EMG signals are collected from 6 age-matched, neurologically intact healthy subjects and 10 stroke patients, while the target force space is divided into 8 subspaces. According to the results of muscle synergy identification with non-negative matrix factorization algorithm, muscle pairs are classified as synergistic and non-synergistic. In both control and stroke groups, IMC is then calculated for all available muscle pairs. The results show that synergistic muscle pairs have higher coherence in both groups. Furthermore, anterior and middle deltoids, identified as synergistic muscles in both groups, exhibited significantly weaker IMC at alpha band in stroke patients. The anterior and posterior deltoids, identified as synergistic muscles only in stroke patients, revealed significantly higher IMC in stroke group at low gamma band. On the contrary, anterior deltoid and pectoralis major, identified as synergistic muscles in control group only, revealed significantly higher IMC in control group in alpha band. The results of muscle synergy and IMC analyses provide congruent and complementary information for investigating the mechanism that underlies post-stroke motor recovery.


Insights into the climate-driven evolution of gas hydrate-bearing permafrost sediments: implications for prediction of environmental impacts and security of energy in cold regions.
The present study investigates the evolution of gas hydrate-bearing permafrost sediments against the environmental temperature change. The elastic wave velocities and effective thermal conductivity (ETC) of simulated gas hydrate-bearing sediment samples were measured at a typical range of temperature in permafrost and wide range of hydrate saturation. The experimental results reveal the influence of several complex and interdependent pore-scale factors on the elastic wave velocities and ETC. It was observed that the geophysical and geothermal properties of the system are essentially governed by the thermal state, saturation and more significantly, pore-scale distribution of the co-existing phases. In particular, unfrozen water content substantially controls the heat transfer at sub-zero temperatures close to the freezing point. A conceptual pore-scale model was also proposed to describe the pore-scale distribution of each phase in a typical gas hydrate-bearing permafrost sediment. This study underpins necessity of distinguishing ice from gas hydrates in frozen sediments, and its outcome is essential to be considered not only for development of large-scale permafrost monitoring systems, bus also accurate quantification of natural gas hydrate as a potential sustainable energy resource in cold regions.


Effect of context on respiratory rate measurement in identifying non-severe pneumonia in African children.
Cough or difficult breathing and an increased respiratory rate for their age are the commonest indications for outpatient antibiotic treatment in African children. We aimed to determine whether respiratory rate was likely to be transiently raised by a number of contextual factors in a busy clinic leading to inaccurate diagnosis. Respiratory rates were recorded in children aged 2-59 months presenting with cough or difficulty breathing to one of the two busy outpatient clinics and then repeated at 10-min intervals over 1 h in a quiet setting. One hundred and sixty-seven children were enrolled with a mean age of 7.1 (SD ± 2.9) months in infants and 27.6 (SD ± 12.8) months in children aged 12-59 months. The mean respiratory rate declined from 42.3 and 33.6 breaths per minute (bpm) in the clinic to 39.1 and 32.6 bpm after 10 min in a quiet room and to 39.2 and 30.7 bpm (P < 0.001) after 60 min in younger and older children, respectively. This resulted in 11/13 (85%) infants and 2/15 (13%) older children being misclassified with non-severe pneumonia. In a random effects linear regression model, the variability in respiratory rate within children (42%) was almost as much as the variability between children (58%). Changing the respiratory rates cut-offs to higher thresholds resulted in a small reduction in the proportion of non-severe pneumonia mis-classifications in infants. Noise and other contextual factors may cause a transient increase in respiratory rate and consequently misclassification of non-severe pneumonia. However, this effect is less pronounced in older children than infants. Respiratory rate is a difficult sign to measure as the variation is large between and within children. More studies of the accuracy and utility of respiratory rate as a proxy for non-severe pneumonia diagnosis in a busy clinic are needed.


Mie scattering, Maxwell Garnett theory, and the Giaever immunology slide.
The physical mechanism whereby adsorbed layers of transparent material cause a visual darkening of thin indium films is investigated. The indium is observed to be in the form of discrete islands. The wavelength of minimum optical transmission through the indium film does not vary proportionately with the size of the indium island size, as would be expected if Mie scattering were the dominant optical effect. Instead, this wavelength depends on the fractional volume of the indium film occupied by the indium islands themselves, in the manner predicted by Maxwell Garnett theory.


A herpesvirus of rhesus monkeys related to the human Kaposi's sarcoma-associated herpesvirus.
A herpesvirus that is related to but distinct from the Kaposi's sarcoma-associated herpesvirus (KSHV, or human herpesvirus 8) was isolated from rhesus monkeys. The sequence of 10.6 kbp from virion DNA revealed the presence of an interleukin-6 homolog similar to what is present in KSHV and a closer relatedness of the DNA polymerase and glycoprotein B reading frames to those of KSHV than to those of any other herpesvirus. This rhesus monkey herpesvirus replicated lytically and to high titers in cultured rhesus monkey fibroblasts. Antibody testing revealed a high prevalence for at least 10 years in our rhesus monkey colony and a high prevalence in two other colonies that were tested. Thus, rhesus monkeys naturally harbor a virus related to KSHV, which we have called RRV, for rhesus monkey rhadinovirus.


Implications of fibrinogenolysis in patients with closed head injury.
The objective of this study was to determine the clinical significance of fibrinogenolysis in patients with isolated closed head injury. We correlated indices of fibrinolytic activity, fibrinogen degradation products (FgDP), and fibrin degradation products (FbDP) with outcome in order to accomplish this. This study consisted of 40 patients with isolated closed head trauma in whom blood sampling could be initiated within 3 h after injury. Patients were divided into two groups according to Glasgow Outcome Scale status at 3 months after injury, characterized as good recovery or moderate disability (group 1, n = 21); and severe disability, vegetative, or death (group 2, n = 19). The plasma fibrinogen concentration correlated with the Glasgow Coma Scale score on admission (r2 = 0.201, p < 0.01), and plasma fibrinogen concentrations in group 2 were lower than in group 1 (p < 0.05). Plasma concentrations of fibrin/fibrinogen degradation products (FDP) and plasmin-alpha2-plasmin inhibitor complex (PIC), molecular markers of activation of fibrinolysis, were higher in group 2 than in group 1 (p < 0.001), and both FgDP and FbDP concentrations in group 2 also were higher than in group 1 (p < 0.001). Both the FgDP and FbDP concentrations correlated with the PIC concentration. Moreover, the plasma FgDP concentrations correlated inversely with alpha2-plasmin inhibitor activity, a potent inhibitor of the fibrinolytic sysytem, as did the FbDP concentration. This study reveals that both fibrinolysis and fibrinogenolysis are involved in the coagulopathy that develops during the acute phase of head injury and correlate with fibrinolytic activity. Decreased activity of alpha2-plasmin inhibitor may contribute to fibrinogenolysis.


The influence of comorbid personality disorder on the effects of behavioural activation vs. antidepressant medication for major depressive disorder: results from a randomized trial in Iran.
There is a disagreement about the impact of personality disorder (PD) on treatment outcome for patients with major depressive disorder (MDD). 100 out-patients with MDD were randomized to 16 sessions of behavioural activation (BA) (n = 50) or antidepressant medication (ADM) (n = 50) in Iran. Main outcome was depression severity, measured with the Beck Depression Inventory (BDI-II) and the Hamilton Rating Scale for Depression (HRSD), and assessed at 0, 4, 13 and 49 weeks. Participants with comorbid PDs had higher scores on BDI and HRSD at baseline and throughout the study than participants without comorbid PD. Patients with and without comorbid personality pathology responded equally to treatment on the short-and the long-term. Overall, BA was better in reducing symptoms in patients but this effect was not influenced by comorbid PD. Similar effects were found for a dimensional PD-measure. Only cluster-C PD-traits turned out to be associated with overall depression severity. Cluster-A PD-traits predicted poorer long-term treatment response to ADM and BA, but only on the BDI, not on the HRSD. No effects of cluster-B PD-traits were found. However, PD was associated with higher dropout. The general conclusion is that comorbid PD pathology, especially from cluster-C, is associated with higher depression severity, but not with less response to treatment. Comorbid PD did predict increased chance of dropout.


[Capacities of ultrasound study in a follow-up of patients with lower extremity varicose veins after phlebectomy].
The study was undertaken to estimate the capacities of triplex ultrasound angioscanning in patients with lower extremity varicose veins in the late period after phlebectomy. Seventy patients operated on for the underlying disease were examined. According to the duration of the underlying disease, all the patients were divided into 4 groups: 1) 4 (5.7%) patients had a 5-year history of lower limb varicose veins; 2) 16 (22.9%) had a 5-to-15-year history; 3) 42 (60%) had a 15-to-25-year history; 4) 8 (11.4%) had a more than 25-year history. The ultrasonic marker of recurrent lower limb varicose veins was the re-emergence of dilated saphenous and perforating veins, as well as valve apparatus failure in the operated leg. In groups 1, 2, and 3, a recurrence of the underlying disease was detected just 2 years after surgical treatment. Good results could be obtained with multimodality treatment: phlebosclerotherapy at early stages of the disease, followed by phlebectomy, or multiple phlebosclerotherapy from the earliest stages. Ultrasound study (USS) is the most rational method for screening diagnosis in case of abnormal veins of the lower extremities in the postoperative period. USS carried out at early disease stages and in the postoperative period permits prevention of recurrent lower limb varicose veins.


The role of oxidative stress genes and effect of pH on methylene blue sensitized photooxidation of Escherichia coli.
In this study, the survival time of wild type E. coli W3110 and 11 mutants was analysed with a plate count method in methylene blue added or control groups under daylight fluoroscence illumination (4950 lux) at different pH values (5.0, 6.0, 7.0, and 8.0) in phosphate buffer. As a result, while the number of bacteria did not decrease under photooxidative stress at pH 5.0 and 6.0 during a 6-hour incubation, the wild type and all mutants decreased more than 2 log. at pH 8.0, and approximately one log. at pH 7.0. It was determined that a 2 log decrease in wild type E. coli takes 3.7 h according to t99 value at pH 8, these values were 2.39 h in the katE mutant, 2.64 h in the soxR mutant, 2.67 h in the oxyR mutant, 2.71 h in the sodB mutant, 3 h in the btuE mutant, 3.38 h in the zwf mutant and 3.40 h in the soxS mutant, respectively (p < 0.05). The roles of these genes were proved with complement tests. Finally, it is found that the effectiveness of photooxidative stress is in direct relation with pH, and the katE, soxR, oxyR, sodB, btuE, zwf, and soxS genes are important for the protection against this stress.


Transcriptional profiling of the heart reveals chamber-specific gene expression patterns.
Cardiac chamber-specific gene expression is critical for the normal development and function of the heart. To investigate the genetic basis of cardiac anatomical specialization, we have undertaken a nearly genome-wide transcriptional profiling of the four heart chambers and the interventricular septum. Rigorous statistical analysis has allowed the identification of known and novel members of gene families that are felt to be important in cardiac development and function, including LIM proteins, homeobox proteins, wnt and T-box pathway proteins, as well as structural proteins like actins and myosins. In addition, these studies have allowed the identification of thousands of additional differentially expressed genes, for which there is little structural or functional information. Clustering of genes with known and unknown functions provides insights into signaling pathways that are essential for development and maintenance of chamber-specific features. To facilitate future research in this area, a searchable internet database has been constructed that allows study of the chamber-specific expression of any gene represented on this comprehensive microarray. It is anticipated that further study of genes identified through this effort will provide insights into the specialization of heart chamber tissues, and their specific roles in cardiac development, aging, and disease.


Cardiomyocyte Specific Deletion of ADAR1 Causes Severe Cardiac Dysfunction and Increased Lethality.
Background: Adenosine deaminase acting on RNA 1 (ADAR1) is a double-stranded RNA-editing enzyme that is involved in several functions including the deamination of adenosine to inosine, RNA interference (RNAi) mechanisms and microRNA (miRNA) processing, rendering ADAR1 essential for life. Methods and Results: To investigate whether maintenance of ADAR1 expression is required for normal myocardial homeostasis, we bypassed the early embryonic lethality of ADAR1-null mice through the use of a tamoxifen-inducible Cre recombinase under the control of the cardiac-specific α-myosin heavy chain promoter (αMHC). Targeted ADAR1 deletion in adult mice caused a significant increase in lethality accompanied by severe ventricular remodeling and quick and spontaneous cardiac dysfunction, induction of stress markers and overall reduced expression of miRNAs. Administration of a selective inhibitor of the unfolded protein response (UPR) stress significantly blunted the deleterious effects and improved cardiac function thereby prolonging animal survival. In vitro restoring miR-199a-5p levels in cardiomyocytes lacking ADAR1 diminished UPR activation and concomitant apoptosis. Conclusions: Our findings demonstrate an essential role for ADAR1 in cardiomyocyte survival and maintenance of cardiac function through a mechanism that integrates ADAR1 dependent miRNA processing and the suppression of UPR stress.


Near-field coded-mask technique and its potential for proton therapy monitoring.
Prompt-gamma imaging encompasses several approaches to the online monitoring of the beam range or deposited dose distribution in proton therapy. We test one of the imaging techniques - a coded mask approach - both experimentally and via simulations.
Approach. Two imaging setups have been investigated experimentally. Each of them comprised a structured tungsten collimator in the form of a MURA mask and a LYSO:Ce scintillation detector of fine granularity. The setups differed in detector dimensions and operation mode (1D or 2D imaging). A series of measurements with radioactive sources have been conducted, testing the performance of the setups for near-field gamma imaging. Additionally, Monte Carlo simulations of a larger setup of the same type were conducted, investigating its performance with a realistic gamma source distribution occurring during proton therapy.
Main results. The images of point-like sources reconstructed from two small-scale prototypes' data using the MLEM algorithm constitute the experimental proof of principle for the near-field coded-mask imaging modality, both in the 1D and the 2D mode. Their precision allowed us to calibrate out certain systematic offsets appearing due to the limited alignment accuracy of setup elements. The simulation of the full-scale setup yielded a mean distal falloff retrieval precision of 0.72 mm in the studies for beam energy range 89.5-107.9 MeV and with 1 × 108protons (a typical number for distal spots). The implemented algorithm of image reconstruction is relatively fast - a typical procedure needs several seconds.
Significance. Coded-mask imaging appears a valid option for proton therapy monitoring. The results of simulations let us conclude that the proposed full-scale setup is competitive with the knife-edge-shaped and the multi-parallel slit cameras investigated by other groups.


A Plasma Metabolite Score Related to Psychological Distress and Diabetes Risk: A Nested Case-control Study in US Women.
Psychological distress has been linked to diabetes risk. Few population-based, epidemiologic studies have investigated the potential molecular mechanisms (e.g., metabolic dysregulation) underlying this association. To evaluate the association between a metabolomic signature for psychological distress and diabetes risk. We conducted a nested case-control study of plasma metabolomics and diabetes risk in the Nurses' Health Study, including 728 women (mean age: 55.2 years) with incident diabetes and 728 matched controls. Blood samples were collected between 1989-1990 and incident diabetes was diagnosed between 1992-2008. Based on our prior work, we calculated a weighted plasma metabolite-based distress score (MDS) comprised of 19 metabolites. We used conditional logistic regression accounting for matching factors and other diabetes risk factors to estimate odds ratios (OR) and 95% CI for diabetes risk according to MDS. After adjusting for sociodemographic factors, family history of diabetes, and health behaviors, the OR (95% CI) for diabetes risk across quintiles of the MDS was 1.00 (reference) for Q1, 1.16 (0.77, 1.73) for Q2, 1.30 (0.88, 1.91) for Q3, 1.99 (1.36, 2.92) for Q4, and 2.47 (1.66, 3.67) for Q5. Each SD increase in MDS was associated with 36% higher diabetes risk (95% CI: 1.21, 1.54; p-trend<0.0001). This association was moderately attenuated after additional adjustment for BMI (comparable OR: 1.17; 95% CI: 1.02, 1.35; p-trend=0.02). The MDS explained 17.6% of the association between self-reported psychological distress (defined as presence of depression or anxiety symptoms) and diabetes risk (p=0.04). MDS was significantly associated with diabetes risk in women. These results suggest that differences in multiple lipid and amino acid metabolites may underlie the observed association between psychological distress and diabetes risk.


Dimethyl sulfide in the surface ocean and the marine atmosphere: a global view.
Dimethyl sulfide (DMS) has been identified as the major volatile sulfur compound in 628 samples of surface seawater representing most of the major oceanic ecozones. In at least three respects, its vertical distribution, its local patchiness, and its distribution in oceanic ecozones, the concentration of DMS in the sea exhibits a pattern similar to that of primary production. The global weightedaverage concentration of DMS in surface seawater is 102 nanograms of sulfur (DMS) per liter, corresponding to a global sea-to-air flux of 39 x 10(12) grams of sulfur per year. When the biogenic sulfur contributions from the land surface are added, the biogenic sulfur gas flux is approximately equal to the anthropogenic flux of sulfur dioxide. The DMS concentration in air over the equatorial Pacific varies diurnally between 120 and 200 nanograms of sulfur (DMS) per cubic meter, in agreement with the predictions of photochemical models. The estimated source flux of DMS from the oceans to the marine atmosphere is in agreement with independently obtained estimates of the removal fluxes of DMS and its oxidation products from the atmosphere.


Risk factors for idiosyncratic drug-induced liver injury.
Idiosyncratic drug-induced liver injury (DILI) is a rare disorder that is not related directly to dosage and little is known about individuals who are at increased risk. There are no suitable preclinical models for the study of idiosyncratic DILI and its pathogenesis is poorly understood. It is likely to arise from complex interactions among genetic, nongenetic host susceptibility, and environmental factors. Nongenetic risk factors include age, sex, and other diseases (eg, chronic liver disease or human immunodeficiency virus infection). Compound-specific risk factors include daily dose, metabolism characteristics, and propensity for drug interactions. Alcohol consumption has been proposed as a risk factor for DILI from medications, but there is insufficient evidence to support this. Many studies have explored genetic defects that might be involved in pathogenesis and focused on genes involved in drug metabolism and the immune response. Multicenter databases of patients with DILI (the United States Drug Induced Liver Injury Network, DILIGEN, and the Spanish DILI registry) are important tools for clinical and genetic research. A genome-wide association study of flucloxacillin hepatotoxicity has yielded groundbreaking results and many similar studies are underway. Nonetheless, DILI is challenging to investigate because of its rarity, the lack of experimental models, the number of medications that might cause it, and challenges to diagnosis.


Not just full of hot air: hyperbaric oxygen therapy increases survival in cases of necrotizing soft tissue infections.
The utility of hyperbaric oxygen therapy (HBOT) in the treatment of necrotizing soft tissue infections (NSTIs) has not been proved. Previous studies have been subject to substantial selection bias because HBOT is not available universally at all medical centers, and there is often considerable delay associated with its initiation. We examined the utility of HBOT for the treatment of NSTI in the modern era by isolating centers that have their own HBOT facilities. We queried all centers in the University Health Consortium (UHC) database from 2008 to 2010 that have their own HBOT facilities (n=14). Cases of NSTI were identified by International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes, which included Fournier gangrene (608.83), necrotizing fasciitis (728.86), and gas gangrene (040.0). Status of HBOT was identified by the presence (HBOT) or absence (control) of ICD-9 procedure code 93.95. Our cohort was risk-stratified and matched by UHC's validated severity of illness (SOI) score. Comparisons were then made using univariate tests of association and multivariable logistic regression. There were 1,583 NSTI cases at the 14 HBOT-capable centers. 117 (7%) cases were treated with HBOT. Univariate analysis showed that there was no difference between HBOT and control groups in hospital length of stay, direct cost, complications, and mortality across the three less severe SOI classes (minor, moderate, and major). However, for extreme SOI the HBOT group had fewer complications (45% vs. 66%; p<0.01) and fewer deaths (4% vs. 23%; p<0.01). Multivariable analysis showed that patients who did not receive HBOT were less likely to survive their index hospitalization (odds ratio, 10.6; 95% CI 5.2-25.1). At HBOT-capable centers, receiving HBOT was associated with a significant survival benefit. Use of HBOT in conjunction with current practices for the treatment of NSTI can be both a cost-effective and life-saving therapy, in particular for the sickest patients.


A Multi-Criteria Framework for Pandemic Response Measures.
In managing the COVID-19 pandemic, several compelling narratives seem to have played a significant role in the decision-making processes regarding which risk mitigation and management measures to implement. Many countries were to a large extent unprepared for such a situation, even though predictions about a significant probability for a pandemic to occur existed, and national governments of several countries often acted in an uncoordinated manner, which resulted in many inconsistencies in the disaster risk reduction processes. Limited evidence has also made room for strategic narratives meant to persuade the public of the chosen set of actions, even though the degree of uncertainty regarding the outcomes of these was high, further complicating the situation. In this article, we assume a normative standpoint regarding rhapsodic decision making and suggest an integrated framework for a more elaborated decision analysis under the ambiguity of how to contain the virus spread from a policy point of view, while considering epidemiologic estimations and socioeconomic factors in a multi-stakeholder-multi-criteria context based on a co-creative work process for eliciting attitudes, perceptions, as well as preferences amongst relevant stakeholder groups. The framework, applied in our paper on Romania for demonstrative purposes, is used for evaluating mitigation measures for catastrophic events such as the COVID-19 situation, to mobilize better response strategies for future scenarios related to pandemics and other hazardous events, as well as to structure the production and analysis of narratives on the current pandemic effects.


Vitamin K in the treatment and prevention of osteoporosis and arterial calcification.
The role of vitamin K in the prevention and treatment of osteoporosis and arterial calcification is examined. Vitamin K is essential for the activation of vitamin K-dependent proteins, which are involved not only in blood coagulation but in bone metabolism and the inhibition of arterial calcification. In humans, vitamin K is primarily a cofactor in the enzymatic reaction that converts glutamate residues into gamma-carboxyglutamate residues in vitamin K-dependent proteins. Numerous studies have demonstrated the importance of vitamin K in bone health. The results of recent studies have suggested that concurrent use of menaquinone and vitamin D may substantially reduce bone loss. Menaquinone was also found to have a synergistic effect when administered with hormone therapy. Several epidemiologic and intervention studies have found that vitamin K deficiency causes reductions in bone mineral density and increases the risk of fractures. Arterial calcification is an active, cell-controlled process that shares many similarities with bone metabolism. Concurrent arterial calcification and osteoporosis have been called the "calcification paradox" and occur frequently in postmenopausal women. The results of two dose-response studies have indicated that the amount of vitamin K needed for optimal gamma-carboxylation of osteocalcin is significantly higher than what is provided through diet alone and that current dosage recommendations should be increased to optimize bone mineralization. Few adverse effects have been reported from oral vitamin K. Phytonadione and menaquinone may be effective for the prevention and treatment of osteoporosis and arterial calcification.


Identification of the Mesorhizobium loti gene responsible for glycerophosphorylation of periplasmic cyclic beta-1,2-glucans.
Periplasmic cyclic beta-1,2-glucans play a crucial role in symbiosis as well as in hypo-osmotic adaptation for rhizobia. These glucans are modified in many species by anionic substituents such as glycerophosphoryl and succinyl ones, but their role remains to be examined. In this work, the cgmA homolog is shown to be responsible for glycerophosphorylation of cyclic beta-1,2-glucans in Mesorhizobium loti. The mutation in cgmA converted most anionic glucans into neutral ones, leaving a small amount of succinylated ones. An additional mutation in opgC, which encodes a succinyltransferase homolog, abolished the residual succinyl substituents in the cgmA-mutant background. The double mutant in cgmA and opgC did not show any significant phenotypic differences from the wild type during both vegetative growth and symbiosis. It is concluded that the anionic substituents make a minor contribution, if any, to the effectiveness of cyclic beta-1,2-glucans in M. loti.


Rebound intracranial hypertension: a complication of epidural blood patching for intracranial hypotension.
Rebound intracranial hypertension is a complication of epidural blood patching for treatment of intracranial hypotension characterized by increased intracranial pressure, resulting in potentially severe headache, nausea, and vomiting. Because the symptoms of rebound intracranial hypertension may bear some similarity to those of intracranial hypotension and literature reports of rebound intracranial hypertension are limited, it may be mistaken for refractory intracranial hypotension, leading to inappropriate management. This clinical report of 9 patients with confirmed rebound intracranial hypertension reviews the clinical characteristics of patients with this condition, emphasizing factors that can be helpful in discriminating rebound intracranial hypertension from refractory spontaneous intracranial hypotension, and discusses treatment.


[Genetics of the immune response of karakul sheep vaccinated with colibacillosis and salmonellosis vaccines. II. An analysis of the intensity of the immune response in 1st-generation hybrids].
In experiments on hybrid karakul sheep immunized with E. coli and Salmonella vaccines immune response in hybrids F1, obtained from parents oppositely reacting to these vaccines, has been analyzed. The intensity of immune response in karakul sheep has been shown to be inherited as a dominant characteristic, not linked with sex, and regulated, seemingly, by a relatively small number of Ir genes. The content of EA- and EAC-rosetteforming cells does not depend on the intensity of immune response to any of the antigens.


A robust and sensitive metric for quantifying movement smoothness.
The need for movement smoothness quantification to assess motor learning and recovery has resulted in various measures that look at different aspects of a movement's profile. This paper first shows that most of the previously published smoothness measures lack validity, consistency, sensitivity, or robustness. It then introduces and evaluates the spectral arc-length metric that uses a movement speed profile's Fourier magnitude spectrum to quantify movement smoothness. This new metric is systematically tested and compared to other smoothness metrics, using experimental data from stroke and healthy subjects as well as simulated movement data. The results indicate that the spectral arc-length metric is a valid and consistent measure of movement smoothness, which is both sensitive to modifications in motor behavior and robust to measurement noise. We hope that the systematic analysis of this paper is a step toward the standardization of the quantitative assessment of movement smoothness.


Generation of Highly Selective, Potent, and Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors.
The ability of G protein-coupled receptor (GPCR) kinases (GRKs) to regulate the desensitization of GPCRs has made GRK2 and GRK5 attractive targets for treating diseases such as heart failure and cancer. Previously, our work showed that Cys474, a GRK5 subfamily-specific residue located on a flexible loop adjacent to the active site, can be used as a covalent handle to achieve selective inhibition of GRK5 over GRK2 subfamily members. However, the potency of the most selective inhibitors remained modest. Herein, we describe a successful campaign to adapt an indolinone scaffold with covalent warheads, resulting in a series of 2-haloacetyl-containing compounds that react quickly and exhibit three orders of magnitude selectivity for GRK5 over GRK2 and low nanomolar potency. They however retain a similar selectivity profile across the kinome as the core scaffold, which was based on Sunitinib.


Combined RNA interference and gene replacement therapy targeting MFN2 as proof of principle for the treatment of Charcot-Marie-Tooth type 2A.
Mitofusin-2 (MFN2) is an outer mitochondrial membrane protein essential for mitochondrial networking in most cells. Autosomal dominant mutations in the MFN2 gene cause Charcot-Marie-Tooth type 2A disease (CMT2A), a severe and disabling sensory-motor neuropathy that impacts the entire nervous system. Here, we propose a novel therapeutic strategy tailored to correcting the root genetic defect of CMT2A. Though mutant and wild-type MFN2 mRNA are inhibited by RNA interference (RNAi), the wild-type protein is restored by overexpressing cDNA encoding functional MFN2 modified to be resistant to RNAi. We tested this strategy in CMT2A patient-specific human induced pluripotent stem cell (iPSC)-differentiated motor neurons (MNs), demonstrating the correct silencing of endogenous MFN2 and replacement with an exogenous copy of the functional wild-type gene. This approach significantly rescues the CMT2A MN phenotype in vitro, stabilizing the altered axonal mitochondrial distribution and correcting abnormal mitophagic processes. The MFN2 molecular correction was also properly confirmed in vivo in the MitoCharc1 CMT2A transgenic mouse model after cerebrospinal fluid (CSF) delivery of the constructs into newborn mice using adeno-associated virus 9 (AAV9). Altogether, our data support the feasibility of a combined RNAi and gene therapy strategy for treating the broad spectrum of human diseases associated with MFN2 mutations.


Reevaluation of testicular biopsies of males with nonobstructive azoospermia in assisted reproductive technology.
Spermatogenesis was investigated in seminiferous tubules of 100 males with nonobstructive azoospermia. Forty-four (44%) cases had Sertoli-cell-only syndrome, 23 (23%) had spermatogonium in the tubules, 17 (17%) had primary spermatocyte in the tubules, and 16 (16%) had round or late spermatid in the tubules. No cases showed secondary spermatocyte present in the tubules. The mean serum follicle-stimulating hormone (FSH) in males with nonobstructive azoospermia was significantly higher than that in males with obstructive azoospermia (p < .001). The mean concentrations of serum FSH in cases with Sertoli-cell-only syndrome and spermatogonium in the tubules were significantly higher than those in cases with primary spermatocyte and spermatid in the tubules (p < .05-.001). The results indicate that the evaluation of testicular histology using the type of germ cells present in seminiferous tubules is available for assisted reproductive technology.


Persistent inflammation leads to proliferative neoplasia and loss of smooth muscle cells in a prostate tumor model.
In prostate cancers, epidemiological data suggest a link between prostate inflammation and subsequent cancer development, but proof for this concept in a tumor model is lacking. A constitutively active version of IκB kinase 2 (IKK2), which is activated by many inflammatory stimuli, was expressed specifically in the prostate epithelium. Constitutive activation of the IKK2/nuclear factor κB axis was insufficient for prostate transformation. However, in combination with heterozygous loss of phosphatase and tensin homolog, IKK2 activation led to an increase in tumor size, formation of cribriform structures, and increase in fiber in the fibroblastic stroma. This phenotype was coupled with persistent inflammation evoked by chemokine expression in the epithelium and stroma. The hyperplastic and dysplastic epithelia correlated with changes evoked by decreased androgen receptor activation. Conversely, inflammation correlated with stromal changes highlighted by loss of smooth muscle cells around prostate ducts. Despite the loss of the smooth muscle barrier, tumors were rarely invasive in a C57BL/6 background. Data mining revealed that smooth muscle markers are also downregulated in human prostate cancers, and loss of these markers in primary tumors is associated with subsequent metastasis. In conclusion, our data show that loss of smooth muscle and invasiveness of the tumor are not coupled in our model, with inflammation leading to increased tumor size and a dedifferentiated stroma.


High-dose carboplatin, thiotepa, and etoposide with autologous stem cell rescue for patients with previously irradiated recurrent medulloblastoma.
Recurrent medulloblastoma is highly lethal in previously irradiated patients. Previously irradiated patients with M-0-M-3 recurrences who achieved a minimal disease state prior to protocol enrollment received carboplatin (Calvert formula with area under the curve = 7 mg/mL min, maximum 500 mg/m(2)/day) on days -8 to -6, and thiotepa (300 mg/m(2)/day) and etoposide (250 mg/m(2)/day) on days -5 to -3, followed by autologous stem cell rescue (ASCR) on day 0. Twenty-five patients, aged 7.6-44.7 years (median 13.8 years) at ASCR, were treated. Three (12%) died of treatment-related toxicities within 30 days of ASCR, due to multiorgan system failure (n = 2) and aspergillus infection with veno-occlusive disease (n = 1). Tumor recurred in 16 at a median of 8.5 months (range 2.3-58.5 months). Six are event-free survivors at a median of 151.2 months post-ASCR (range 127.2-201.6 months). The Kaplan-Meier estimate of median overall survival is 26.8 months (95% CI: 11.9-51.1 months) and of event-free survival (EFS) and overall survival are both 24% (95% CI: 9.8%-41.7%) at 10 years post-ASCR. M-0 (vs M-1 + ) recurrence prior to protocol, lack of tissue confirmation of relapse, and initial therapy of radiation therapy (RT) alone (vs RT + chemotherapy) were not significantly associated with better EFS (P = .33, .34, and .27, respectively). Trends toward better EFS were noted in patients (n = 5) who received additional RT as part of their retrieval therapy (P = .07) and whose recurrent disease was demonstrated to be sensitive to reinduction chemotherapy (P = .09). This retrieval strategy provides long-term EFS for some patients with previously irradiated recurrent medulloblastoma. The use of additional RT may be associated with better outcome.


Prone mammoPET acquisition improves the ability to fuse MRI and PET breast scans.
This study compared prone acquisition of PET scans with traditional supine acquisition to improve fusion of PET scans with MRI scans and improve evaluation of enhancing breast lesions detected on MRI. MRI breast scans are acquired in the prone position using a breast coil to allow the breasts to hang pendant. An apparatus was fabricated to allow prone acquisition of PET scans. Fused scans from 2 patients acquired both prone and supine were contrasted with those from 3 patients acquired supine only. All 5 MRI scans were acquired on standard scanners. The PET scans were acquired with a PET/CT unit using a low-dose CT scan for attenuation correction. The PET and MRI volumes were matched twice (using a semiautomated registration method) by different operators. The additional value of fusion was judged using reports from the original (nonfused) MRI and PET, joint rereading of the volumes side by side, and examination of fused images. Of 12 enhancing lesions on breast MRI, 7 demonstrated uptake on PET/CT. In the 3 supine-only cases, the fused images were not interpretable because of the marked distortion of the breasts. In the 2 prone cases, the fused images increased our confidence in characterizing a lesion as benign or malignant. Interpretations were confirmed by clinical follow up in 2 or histologic results in 3 patients. PET MRI fusion is feasible and may assist in localizing lesions detected on either study. A more extensive study is underway to confirm the value of this fusion technique.


Bird Migration: Influence of Physiological State upon Celestial Orientation.
By means of photoperiod manipulation, the physiological states of spring and autumn migratory readiness were induced in indigo buntings. The orientational tendencies of these two groups of birds were tested simultaneously in May 1968, under an artificial, spring planetarium sky. Birds in spring condition oriented northward; those in autumnal condition, southward. These results suggest that changes in the internal physiological state of the bird rather than differences in the external stimulus situation are responsible for the seasonal reversal of preferred migration direction in this species.


Electronic structure of mono(Lewis base)-stabilized borylenes.
This work demonstrates that the mono(Lewis base)-stabilized three-center-six-electron (3c-6e) or LB → B-R type borylenes may have a ground state singlet (σ2π0 and σ0π2) or triplet (σ1π1) electronic structure, depending on the substitution group, Lewis base, and molecule topology (cyclic or acyclic). The singlet-triplet energy gap of a borylene increases with electron-donating substitution groups and decreases with Lewis bases of strong σ-donating and π-accepting feature (e.g., carbenes and pyridine). The gap can be widely varied (ranging up to about 300 kJ mol-1) and even inversed by the proper combination of substitution groups and Lewis bases. These borylenes may even have singlet-and-triplet coexisting ground state electronic structures, which imply their complex reactivity.


Rheumatic heart disease in Nigerian children: clinical and preventive aspects.
Ninety-two children with rheumatic heart disease were studied clinically, and through a post-diagnosis surveillance period of varying duration over a 10-year period. The logistics and effectiveness of secondary penicillin prophylaxis, administered monthly, were assessed during the surveillance period. Eighty-one (88%) of the 92 children were seen for the first time with already established rheumatic heart disease. Mitral insufficiency was the major functional defect in these children whose mean age was 8.6 years. There was a high default rate of just under 50% among children referred to the surveillance clinic. Socio-economic inadequacies were found to be major factors in the high default rate. Regular monthly parenteral penicillin was found to be effective in reducing recurrence of rheumatic fever and maintaining good health in these children.


Selective innervation of NK1 receptor-lacking lamina I spinoparabrachial neurons by presumed nonpeptidergic Aδ nociceptors in the rat.
Fine myelinated (Aδ) nociceptors are responsible for fast, well-localised pain, but relatively little is known about their postsynaptic targets in the spinal cord, and therefore about their roles in the neuronal circuits that process nociceptive information. Here we show that transganglionically transported cholera toxin B subunit (CTb) labels a distinct set of afferents in lamina I that are likely to correspond to Aδ nociceptors, and that most of these lack neuropeptides. The vast majority of lamina I projection neurons can be retrogradely labelled from the lateral parabrachial area, and these can be divided into 2 major groups based on expression of the neurokinin 1 receptor (NK1r). We show that CTb-labelled afferents form contacts on 43% of the spinoparabrachial lamina I neurons that lack the NK1r, but on a significantly smaller proportion (26%) of those that express the receptor. We also confirm with electron microscopy that these contacts are associated with synapses. Among the spinoparabrachial neurons that received contacts from CTb-labelled axons, contact density was considerably higher on NK1r-lacking cells than on those with the NK1r. By comparing the density of CTb contacts with those from other types of glutamatergic bouton, we estimate that nonpeptidergic Aδ nociceptors may provide over half of the excitatory synapses on some NK1r-lacking spinoparabrachial cells. These results provide further evidence that synaptic inputs to dorsal horn projection neurons are organised in a specific way. Taken together with previous studies, they suggest that both NK1r(+) and NK1r-lacking lamina I projection neurons are directly innervated by Aδ nociceptive afferents.


DNA: reaction with chloroquine.
Diflerence spectrophotometry shows that double-stranded DNA produces mnarked changes in the absorption spectrum of chloroquine; only minor changes occur with single-stranded DNA. A DNA-chloroquine complex was demonstrated to sediment in the analytical ultracentrifuge. Chloroquine strongly elevated the thermal dissociation temperature, T(m), of DNA. It is concluded that the drug forms a complex with DNA by ionic interaction and stabilizes the helix.


Current Status of Women's Health Nursing Practicum and Direction.
This study was done to examine current status of women's health nursing practicum and identify necessary core nursing skills in this practicum area. Moreover, one syllabus and evaluation sheets for women's health nursing clinical practicum at one university were reviewed. A survey design was used with 81 educators who were teaching maternity or women's health nursing and its practicum. Most clinical sites for practicum were university hospitals (43.0%), women's hospitals (32.7%), or general hospitals (17.3%); but the majority (77.8%) of educators expressed difficulty in finding appropriate practicum places. Common teaching and learning methods were clinical guides for practicum (44.6%), e-learning content (30.2%), and simulation (23.6%). Core nursing skills for this practicum included assessment of stages of labor, preparation of uterine-fetal monitoring devices and interpretation of results, monitoring uterus and fetal activity, and performing Leopold's maneuver. For postpartum care, the following were included; postpartum fundal massage, assessment of breast engorgement, fundus height, and episiotomy sites, inserting urinary catheter, and teaching the use of patient-controlled analgesia. To improve the quality of clinical practicum, development of a clear course syllabus, standardized clinical guidebook, and core nursing skills is required and should be shared with all relevant nurse educators.


A comparison of two methods for estimating prevalence ratios.
It is usually preferable to model and estimate prevalence ratios instead of odds ratios in cross-sectional studies when diseases or injuries are not rare. Problems with existing methods of modeling prevalence ratios include lack of convergence, overestimated standard errors, and extrapolation of simple univariate formulas to multivariable models. We compare two of the newer methods using simulated data and real data from SAS online examples. The Robust Poisson method, which uses the Poisson distribution and a sandwich variance estimator, is compared to the log-binomial method, which uses the binomial distribution to obtain maximum likelihood estimates, using computer simulations and real data. For very high prevalences and moderate sample size, the Robust Poisson method yields less biased estimates of the prevalence ratios than the log-binomial method. However, for moderate prevalences and moderate sample size, the log-binomial method yields slightly less biased estimates than the Robust Poisson method. In nearly all cases, the log-binomial method yielded slightly higher power and smaller standard errors than the Robust Poisson method. Although the Robust Poisson often gives reasonable estimates of the prevalence ratio and is very easy to use, the log-binomial method results in less bias in most common situations, and because it fits the correct model and obtains maximum likelihood estimates, it generally results in slightly higher power, smaller standard errors, and, unlike the Robust Poisson, it always yields estimated prevalences between zero and one.


Cognitive behavioural group therapy for adolescents with ADHD: a study of satisfaction and feasibility.
Adolescents with ADHD are at increased risk of adverse outcomes and a negative life trajectory into adulthood. Evidence regarding treatment specifically tailored for the needs of this age group are still limited. High dropout rates, discontinuation of medication and treatment resistance are common issues in this population, and the patient perspective on new treatment options is therefore important. In this study, we aimed to investigate treatment satisfaction and feasibility of a group CBT program for adolescents with ADHD. We further aimed to identify any baseline characteristics predicting satisfaction. This study was part of a larger RCT of group CBT as add-on treatment for adolescents aged 14-18 years (Mean age 15.9 years, SD 1.3) with ADHD in Norway. Satisfaction and feasibility in the treatment group (n = 48) were measured by completion of an evaluation questionnaire, attendance of group sessions and a group-leaders checklist. Predictors of satisfaction were analysed using linear regression. Overall satisfaction was very high with a significant age effect, the eldest participants being most satisfied. Attendance rate was high with few dropouts and medical adherence during the treatment period was good. Group-leaders generally self-evaluated adherence to treatment manual positively but addressing resistance towards homework as challenging. The participants were very satisfied with the group CBT treatment. Treatment options that are accepted and well-liked by the targeted population have the potential of reducing resistance towards treatment, improving future health and adherence to medication. The program is considered suitable for a clinical setting and may represent a feasible treatment supplement for adolescent ADHD.


NKp44-NKp44 Ligand Interactions in the Regulation of Natural Killer Cells and Other Innate Lymphoid Cells in Humans.
Natural Killer (NK) cells are potent cytotoxic cells belonging to the family of Innate Lymphoid Cells (ILCs). Their most characterized effector functions are directed to the control of aberrant cells in the body, including both transformed and virus-infected cells. NK cell-mediated recognition of abnormal cells primarily occurs through receptor-ligand interactions, involving an array of inhibitory and activating NK receptors and different types of ligands expressed on target cells. While most of the receptors have become known over many years, their respective ligands were only defined later and their impressive complexity has only recently become evident. NKp44, a member of Natural Cytotoxicity Receptors (NCRs), is an activating receptor playing a crucial role in most functions exerted by activated NK cells and also by other NKp44+ immune cells. The large and heterogeneous panel of NKp44 ligands (NKp44L) now includes surface expressed glycoproteins and proteoglycans, nuclear proteins that can be exposed outside the cell, and molecules that can be either released in the extracellular space or carried in extracellular vesicles. Recent findings have extended our knowledge on the nature of NKp44L to soluble plasma glycoproteins, such as secreted growth factors or extracellular matrix (ECM)-derived glycoproteins. NKp44L are induced upon tumor transformation or viral infection but may also be expressed in normal cells and tissues. In addition, NKp44-NKp44L interactions are involved in the crosstalk between NK cells and different innate and adaptive immune cell types. NKp44 expression in different ILCs located in tissues further extends the potential role of NKp44-NKp44L interactions.


Dispersion and Diffusion Mechanism of Nanofillers with Different Geometries in Bottlebrush Polymers: Insights from Molecular Dynamics Simulation.
The dispersion and diffusion mechanism of nanofillers in polymer nanocomposites (PNCs) are crucial for understanding the properties of PNCs, which is of great significance for the design of novel materials. Herein, we investigate the dispersion and diffusion behavior of two geometries of nanofillers, namely, spherical nanoparticles (SNPs) and nanorods (NRs), in bottlebrush polymers by utilizing coarse-grained molecular dynamics simulations. With the increase of the interaction strength between the nanofiller and polymer (εnp), both the SNPs and NRs experience a typical "aggregated phase-dispersed phase-bridged phase" state transition in the bottlebrush polymer matrix. We evaluate the validity of the Stokes-Einstein (SE) equation for predicting the diffusion coefficient of nanofillers in bottlebrush polymers. The results demonstrate that the SE predictions are slightly larger than the simulated values for small SNP sizes because the local viscosity that is felt by small SNPs in the densely grafted bottlebrush polymer does not differ much from the macroscopic viscosity. The relative size of the length of the NRs (L) and the radius of gyration (Rg) of the bottlebrush polymer play a key role in the diffusion of NRs. In addition, we characterize the anisotropic diffusion of NRs to analyze their translational and rotational diffusion. The motion of NRs in the direction perpendicular to the end-to-end vector is more hindered, indicating that there is a strong coupling between the rotation of NRs and the motion of the polymer. The NR motion shows stronger anisotropic diffusion at short time scales because of the steric effects generated by side chains of the bottlebrush polymer. In general, our results provide a fundamental understanding of the dispersion of nanofillers and the microscopic mechanism of nanofiller diffusion in bottlebrush polymers.


Recent advances in renal hemodynamics: insights from bench experiments and computer simulations.
It has been long known that the kidney plays an essential role in the control of body fluids and blood pressure and that impairment of renal function may lead to the development of diseases such as hypertension (Guyton AC, Coleman TG, Granger Annu Rev Physiol 34: 13-46, 1972). In this review, we highlight recent advances in our understanding of renal hemodynamics, obtained from experimental and theoretical studies. Some of these studies were published in response to a recent Call for Papers of this journal: Renal Hemodynamics: Integrating with the Nephron and Beyond.


Local recurrence of giant cell tumor of bone after intralesional treatment with and without adjuvant therapy.
The use of adjuvants after curettage has been well established for the treatment of giant cell tumor of bone. The purpose of this study was to analyze the rates of recurrence following different types of treatment as well as the influence of various factors of tumor presentation on those rates. The data regarding benign giant cell tumors of the appendicular skeleton from ten bone tumor centers were evaluated. Axial and malignant tumors were excluded. The recurrence rates associated with the different treatment modalities were analyzed, and hazard ratios for a recurrence were calculated for multiple factors of tumor presentation. The study included 384 surgical procedures, involving 256 primary and 128 recurrent tumors. The mean duration of follow-up was 64.2 months. Wide excision was performed in seventy-eight cases (20.3%), and an intralesional procedure was done in 306 (79.7%). Of the intralesional procedures, 103 (33.7%) were performed without the use of adjuvants, 102 (33.3%) included filling with polymethylmethacrylate, seventy-four (24.2%) included polymethylmethacrylate filling after phenolization, and twenty-seven (8.8%) included use of local toxins. The overall recurrence rate after the intralesional procedures was 49% when no adjuvants had been used, 22% when polymethylmethacrylate only had been used as an adjuvant, 27% when polymethylmethacrylate had been used after phenolization, and 15% when phenol or other local toxins had been used (without polymethylmethacrylate). The highest rate of recurrence (36%) after curettage with adjuvants was associated with extracompartmental tumors. Recurrent tumors were not at increased risk for another recurrence, even when they were extracompartmental. The recurrence rate following curettage of a primary tumor without the use of adjuvants (55%) was higher than that following the same treatment of a recurrent tumor (39%) (p = 0.033). Use of polymethylmethacrylate as an adjuvant significantly reduces the recurrence rate following intralesional treatment of benign giant cell tumors, and it appears to be the therapy of choice for primary as well as recurrent giant cell tumors of bone. The significantly better results following treatment of recurrent tumors without adjuvants compared with the results of the same treatment of primary tumors were probably related to increased surgical thoroughness brought about by the surgeon's awareness of dealing with a riskier tumor.


Off the cuff consultations.
Over six months I recorded 198 off the cuff consultations that occurred at social gatherings, at chance meetings, and in medical settings outside my surgery. More men than women made such consultations, roughly two thirds were a request for health information, and just under half of consultations were with other doctors' patients. It seemed that many patients were seeking a second medical opinion.


Cost and morbidity associated with antibiotic prophylaxis in the ICU.
Although the high cost and inappropriate use of antibiotics have been documented before, we are not aware of any data on nonsurgical site infectious morbidity associated with prolonged courses of prophylactic antibiotics (PA). Data regarding antibiotic orders were collected using a custom designed microbiology database in the Surgical Intensive Care Unit of a teaching hospital from October 1, 1995 through April 30, 1997. The database was retrospectively reviewed. The cost of PA in excess of 1 day was calculated. Frequency of bacteremia and line infections were compared in patients receiving 1 day or less of PA versus more than 4 days of PA. Sixty-one percent of PA orders were continued for more than 1 day. Cost of PA beyond 1 day totaled $44,893. Bacteremia and line infection were more frequent in the patients receiving more than 4 days of PA. There was poor compliance with the protocol of stopping PA at 24 hours. The cost of noncompliance was $44,893. There were more bacteremias and line infections in patients with duration of PA of more than 4 days.


Multiple promoter elements including a novel repressor site modulate expression of the chick ovalbumin gene.
As is the case with many eukaryotic genes, regulation of the chick ovalbumin (Ov) gene involves both positive and negative modulation. Recent studies indicate that positive regulation by steroids entails binding of several proteins to a hormone-response unit called the steroid-dependent regulatory element (SDRE; -892 to -780). In addition, gene activity is suppressed by factor(s) acting through the negative regulatory element (NRE; -308 to -88). Previous data suggested that the NRE is composed of multiple, independently acting negative elements. The goal of the present studies was to define more precisely the locations of these negative elements and to investigate their functional interactions. Transfection analyses of linker scanning mutants revealed a strong repressor site, designated the COUP-adjacent repressor (CAR) site, located between -119 and -111. Gel mobility shift analyses with the CAR element suggested that it may play a role in the developmental regulation of the Ov gene. A weaker repressor element was also identified at about -275. Surprisingly, two positive sites were found, one of which is the binding site for the estrogen-responsive transcription factor delta-EF1. These results demonstrate that the Ov NRE contains not only sites responsible for the repression of the gene but also a positive element that is required for responsiveness to steroid hormones.


A. hierchuntica extract exacerbates genotoxic, cytotoxic, apoptotic and oxidant effects in B16F10 melanoma cells.
Melanoma is a highly malignant tumor caused by melanocytes. Even though melanoma represents just 3% of all skin malignancies, it represents 75% of deaths. Extracts of A. hierchuntica were reported to have anti-inflammatory, hepatoprotective, and anti-melanogenic activities. This study aims to investigate the dose-related relationship and selectivity of the toxic effects of A. hierchuntica extracts (AHE) on melanoma cells and provide a new option that can be used in the future treatment of melanoma. B16F10 Mus musculus malign melanoma cells and L929 Mus musculus healthy fibroblast cells were treated with root and leaf AHEs in a dose-dependent manner. Intracellular glutathione levels, mitochondrial membrane potential activity, apoptosis, genotoxicity, and cytotoxicity of AHE were evaluated. This study is probably the first study to show a significant apoptotic and genotoxic activity of AHE in selected B16F10 cancer cell lines. Mitochondrial membrane potential and glutathione activity of B16F10 and L929 melanoma cells decreased with increasing concentrations of both leaf and root AHEs. However, viability and reactive oxygen species levels showed selectivity especially the AHEs concentrations between 400 μg/mL and 500 μg/mL. This selectivity based on doses was also validated in apoptosis and genotoxicity between healthy and cancer cells (p < 0.001). The results showed that when looking at melanoma-specific, AHE could be a source of inspiration as an active ingredient in future treatment protocols. AHE can be recommended as potential nutraceuticals in the prevention of human melanoma cancer.


Impact of repeated vaccination on vaccine effectiveness against influenza A(H3N2) and B during 8 seasons.
Recent studies suggest that influenza vaccination in the previous season may influence the effectiveness of current-season vaccination, but this has not been assessed in a single population over multiple years. Patients presenting with acute respiratory illness were prospectively enrolled during the 2004-2005 through 2012-2013 influenza seasons. Respiratory swabs were tested for influenza and vaccination dates obtained from a validated registry. Vaccination status was determined for the current, previous, and prior 5 seasons. Vaccine effectiveness (VE) was calculated for participants aged ≥9 years using logistic regression models with an interaction term for vaccination history. There were 7315 enrollments during 8 seasons; 1056 (14%) and 650 (9%) were positive for influenza A(H3N2) and B, respectively. Vaccination during current only, previous only, or both seasons yielded similar protection against H3N2 (adjusted VE range, 31%-36%) and B (52%-66%). In the analysis using 5 years of historical vaccination data, current season VE against H3N2 was significantly higher among vaccinated individuals with no prior vaccination history (65%; 95% confidence interval [CI], 36%-80%) compared with vaccinated individuals with a frequent vaccination history (24%; 95% CI, 3%-41%; P = .01). VE against B was 75% (95% CI, 50%-87%) and 48% (95% CI, 29%-62%), respectively (P = .05). Similar findings were observed when analysis was restricted to adults 18-49 years. Current- and previous-season vaccination generated similar levels of protection, and vaccine-induced protection was greatest for individuals not vaccinated during the prior 5 years. Additional studies are needed to understand the long-term effects of annual vaccination.


Long-read single-molecule RNA structure sequencing using nanopore.
RNA molecules can form secondary and tertiary structures that can regulate their localization and function. Using enzymatic or chemical probing together with high-throughput sequencing, secondary structure can be mapped across the entire transcriptome. However, a limiting factor is that only population averages can be obtained since each read is an independent measurement. Although long-read sequencing has recently been used to determine RNA structure, these methods still used aggregate signals across the strands to detect structure. Averaging across the population also means that only limited information about structural heterogeneity across molecules or dependencies within each molecule can be obtained. Here, we present Single-Molecule Structure sequencing (SMS-seq) that combines structural probing with native RNA sequencing to provide non-amplified, structural profiles of individual molecules with novel analysis methods. Our new approach using mutual information enabled single molecule structural interrogation. Each RNA is probed at numerous bases enabling the discovery of dependencies and heterogeneity of structural features. We also show that SMS-seq can capture tertiary interactions, dynamics of riboswitch ligand binding, and mRNA structural features.


Recessive palmoplantar keratodermas: a tale of wings, hands, hair and cancer.
The palmoplantar keratodermas (PPKs) are a heterogeneous group of disorders of cornification affecting the palms and soles. Of late, a number of rare, recessive PPKs such as odonto-onycho-dermal dysplasia have been elucidated. Surprisingly, these results indicate that correct palmoplantar keratinization depends on intact Wingless (WNT) signalling. WNT was originally discovered in the fruit fly where it is required for wing morphogenesis. This ancient signalling pathway is now emerging as a master regulator of differentiation in a variety of tissues, including the intestine and the hair follicle. It is also becoming increasingly clear that deregulation of WNT signalling is involved in neoplasia. Thus, a single pathway unites several seemingly disparate processes and disorders. The keratodermas are emerging as model systems in which to study WNT signalling. Moreover, as agents that are in the dermatological arsenal can modulate WNT signalling, some insight into its workings is of importance to the practicing dermatologist. In this review, I outline how WNT signalling is involved in epidermal differentiation and skin cancer and what these new insights mean for everyday dermatology.


Role of Specialized Pro-Resolving Mediators in Neuropathic Pain.
Inflammation and neuroinflammation are critical mechanisms in the generation of neuropathic pain that is experienced in several chronic diseases. The aberrant inflammation that triggers this pathophysiologic process can be tracked down to an exacerbated immune response, which establishes a vicious cycle and continuously recruits inflammatory cells by inducing chronic tissue damage. Recently, impairment of the cellular and molecular machinery orchestrated by specialized pro-resolving mediators (SPMs)-i.e., endogenous lipids termed resolvins, protectins, maresins, and lipoxins that confine the inflammatory cascades in space and time during the "resolution of inflammation"-has emerged as a crucial event in the derangement of the inflammatory homeostasis and the onset of chronic inflammation and pain. Indeed, a deviant inflammatory response that is not adequately controlled by the resolution network leads to the overproduction of pro-inflammatory eicosanoids that, opposite to SPMs, lead to neuropathic pain. Interestingly, in the last two decades convincing evidence has demonstrated that SPMs antagonize the in vivo activity of pro-inflammatory eicosanoids and, overall, exert potent anti-hyperalgesic effects in a number of pain-associated paradigms of disease, such as arthritis and chemotherapy-induced peripheral neuropathy, as well as in many experimental models of pain like mechanical allodynia, chemical pain, heat hypersensitivity and phase 1 and 2 inflammatory pain. Of note, accumulated evidence supports a synergy between SPMs and other signalling pathways, such as those mediated by transient receptor potential (TRP) channels and those triggered by opioid receptors, suggesting that the cascade of events where inflammation and pain perception take part might be ways more intricated than originally expected. Here, we aim at presenting a state-of-the-art view of SPMs, their metabolism and signalling, in the context of cellular and molecular pathways associated to neuropathic pain.


[Intra-arterial fibrinolysis of superior mesenteric artery embolism].
Intra arterial fibrinolysis for acute mesenteric embolism. Acute mesenteric ischemia has a poor prognosis because the diagnosis is often too late (greater than 12 h), leading to a difficult surgery in old patients. The lesions of the bowel don't always allow a single operative embolectomy but often need a resection when there is a long time interval between onset of symptoms and therapy. We report a case of acute embolism in the superior mesenteric artery with the clot located in its terminal part. A rapid diagnosis was made by arteriography and intra-arterial fibrinolysis was attempted with success permitting the complete cure of the affection, without sequellae. This treatment is only likely to be successful if it is carried out within 10-12 hours of the onset of clinical signs and symptoms.


Non-swelling hydrogel-based microfluidic chips.
Hydrogel-based microfluidic chips are more biologically relevant than conventional polydimethylsiloxane (PDMS) chips, but the inherent swelling of hydrogels leads to a decrease in mechanical performance and deformation of the as-prepared structure in their manufacture and application processing. Non-swelling hydrogel has, for the first time, been utilized to construct microfluidic chips in this study. It was fabricated by covalently cross-linking the biocompatible copolymer of di-acrylated Pluronic F127 (F127-DA). Thanks to their non-swelling property, the hydrogel-based microfluidic chips maintain their as-prepared mechanical strength and channel morphology when equilibrated in aqueous solution at 37 °C. Moreover, the microfluidic chips are autoclavable and show an appropriately slow degradation rate by remaining stable within 21 days of incubation. Based on these properties, a vessel-on-a-chip was established by seeding human umbilical vein endothelial cells (HUVECs) onto the microchannel surfaces inside the microfluidic chip. Under 6 days of perfusion culture with a physiologically relevant shear stress of 5 dyne per cm2, the HUVECs in the chip show responsivity to fluid shear stress and express higher endothelial functions than the corresponding static culture. Therefore, non-swelling hydrogel-based microfluidic chips could potentially be applicable for cell/tissue-related applications, performing much better than conventional PDMS or existing hydrogel based microfluidic chips.


Collaborating to develop joint water, sanitation and hygiene (WASH) and neglected tropical disease (NTD) sector monitoring: an expert consultation.
Joint monitoring between the water, sanitation and hygiene (WASH) and neglected tropical disease (NTD) sectors presents an opportunity for enhanced collaboration and progress towards shared objectives. Taking forward outputs from global WASH and NTD Roundtables, we engaged experts in a consultative process of identifying measurable priority indicators for joint monitoring. We used a Delphi method for conducting expert consultation and developing consensus. Experts were invited to participate through purposive and snowball sampling, and open solicitation at key sector meetings. Participating WASH and NTDs experts represented a diversity of interest groups, including NTD and WASH field staff and government stakeholders from endemic countries, bilateral and multilateral development agencies, non-governmental organizations, and academic institutions. Four rounds of consultation were conducted via online surveys. Between 55 and 69 experts participated in each round of consultation. Seven core measurable indicators emerged as priorities for inclusion in joint monitoring for the NTD sector. Our findings provide insight on the development and implementation of joint monitoring frameworks that can be integrated into existing programme level monitoring.


Measurement of respiratory burst of TNF and IL-1 cytokine activated murine peritoneal macrophages challenged with Toxoplasma gondii.
In vitro activation of murine peritoneal macrophages by TNF and IL-I cytokines resulted in significant elevation of respiratory burst (toxic oxygen metabolites) in comparison to inactivated cells when challenged with Toxoplasma gondii. These oxygen metabolites have been known to have microbicidal activity and so, they may be the direct cause of intracellular killing of T. gondii tachyzoites. The level of these oxygen metabolites was measured by chemiluminescence index. A possible biotherapeutic role for TNF and IL-1, through this mechanism, was also emphasized.


[Results of radiotherapy in a series of 250 carcinomas of the mucosal surface of the cheek (author's transl)].
This paper presents the results of a retrospective clinical study of 250 cases of monocentric carcinoma of the mucosal surface of the cheek, i.e. all the primaries treated by radiotherapy at our Institute between January 1948 and December 1965. Neoplastic lesions found at follow-up were regarded as marginal recurrences if in the proximity of the treated area and as secondary tumors in other cases. From 1948 to 1957 conventional radium therapy was the usual treatment for the primary tumor whereas from 1958 to 1965 cobalt teletherapy was given most frequently. Surgery was reserved for lymph node metastases when present on clinical examination. In our experience radiotherapy is effective in cancers of the mucosal surface of the cheek, for it checked local spread in 50.9% of cases, however treated and regardless of initial clinical appearance, whereas in the T1-T2 cases the local failure rate dropped to 35.8%. The higher the T level the greater are the difficulties confronting radiotherapy; for more extensive lesions appropriate combination therapy (radiosurgical) in line with the well-defined rules explained in the text is useful. In our experience radiotherapy yields good long term results regardless of T level and even in the more unfavorable cases. Our study confirms the low rate of lymph spread of these carcinomas: over half of the patients were N0 before treatment; only 56.7% of the patients receiving surgical treatment on the neck had histologically positive lymph nodes; there were very few neck recurrences at follow-up; the presence of suspect or frankly metastatic nodes on clinical examination, being movable and homolateral (N1), did not worsen the prognosis. However, considering the techniques used for irradiation of the primary, some patients received a substantial dose to the neck; hence radiotherapy probably played its part in the low rate of neck metastases.


Copper and dyes enhance laccase production in gamma-proteobacterium JB.
Laccase production in gamma-proteobacterium JB was enhanced 13-fold by adding 0.1 mM CuSO(4) 24 h after the onset of growth. Ethidium bromide (2.5 microM), Malachite Green, Phenol Red and Thymol Blue (10 microM each) enhanced laccase production 17-, 19-, 4- and 2-fold, respectively. Among the fourteen aromatic/organic compounds tried, p-aminobenzoic acid and an industrial effluent, from where the organism was isolated, showed 1.2- and 1.26-fold increases in production.


Effect of prostaglandin E2 on the healing of gastric ulcers: a double-blind endoscopic trail.
A double-blind trial was performed to assess the effect of prostaglandin E2 on the healing of gastric ulcers. The prostaglandin preparation was given orally in doses of 1 mg, 6 hourly for two weeks to ten subjects with proven gastric ulcer. The control group consisted of ten subjects with proven gastric ulcer, without prostaglandin treatment. Gastric ulcer healing was assessed endoscopically with a duodenofiberscope. The maximum diameter of the ulcer crater was determined endoscopically just before and after two weeks of treatment. In the prostaglandin group, complete healing was seen in two cases, considerable healing (50% and more) in three cases, and the overall mean healing rate was 42%. In the control group, complete healing was seen in none, considerable healing in one case, and the overall mean healing rate was 14-3%. The difference, statistically, was significant. The results show that prostaglandin E2 is effective in promoting the healing of gastric ulcers.


Factors affecting the expression of carcinoembryonic antigen at the surface of cultured human colon carcinoma cells.
Factors affecting the expression of carcinoembryonic antigen (CEA) at the surface of in vitro human colon carcinoma cells were determined using 125I-labeled antibodies. Binding of specific anti-CEA antibodies resulted in polar redistribution of CEA, followed by endocytosis of most of the CEA-anti-CEA complexes. These processes were temperature and energy dependent. CEA removed from the tumor cell surface by antibody was totally replaced within 6 hr at 37 degrees, and the reexpression of CEA required protein synthesis. Examination of clonally derived subpopulations of various strains of human colon cancer cells indicated that control over the level of cell surface CEA expressed was genetically stable in vitro. CEA expression was enhanced in a low-CEA-producing strain by incorporating theophylline in the culture medium, and the inclusions of bromodeoxyuridine enhanced the expression of a high-CEA-producing strain. The kinetics of enhancement of CEA expression by these two drugs differed. These findings suggest that CEA expression may be controlled by more than a single gene function.


Reverse engineering of ceramic anthropomorphic figurines from the Tumaco archaeological tradition in southwest Colombia.
Traditional studies of archaeological ceramics in Colombia have been largely based on visual and stylistic analyses. Here we introduce frameworks and concepts of reverse engineering as a complementary strategy to develop hypotheses about ceramic manufacture, as a first step to the address possible cross-craft relationships and broader sociocultural parameters affecting technical traditions. Our case study is focused on ceramic figurines recovered from two archaeological sites in southwest Colombia (Inguapí and La Cocotera), both dated to the period of greatest cultural and technological development of the Tumaco tradition (350 BC-AD 350). The results of the analyses including microscopy, XRF, SEM-EDS and XRD revealed two manufacturing pathways within the broader tradition, developed locally and adapted to the natural resources available to each site. These are shown through chemical and mineralogical differences in the raw materials, as well as differences in their preparation and shaping, molding, and modeling processes as observed at the microstructural level. Estimated firing temperatures are under 600°C for La Cocotera, and under 800°C for those of Inguapí, with an inhomogeneous, oxidizing atmosphere probably related to firing in a pit. The superficial characterization shows that all the figurines were painted, with those from Inguapí externally smoothed and polished, and those from La Cocotera covered with a slip. Notwithstanding differences between sites, the ceramic figurines illustrate a particular technical style that undoubtedly conveyed a shared ideological message of cultural affiliation. These results contribute in an innovative way to archaeological ceramic studies in Colombia from a different perspective that is complementary to the more common typological studies.


Cerebral near-infrared spectroscopy for early recognition of impending cardiac tamponade in a preterm neonate.
Cardiac tamponade is a rare but life-threatening complication of umbilical venous catheter (UVC) placement in neonates. Mortality rates are high; therefore, early diagnosis is important. We present a case of a preterm infant with a UVC in situ who underwent a laparotomy on the first day of life for pneumoperitoneum secondary to meconium ileus. The operation was uneventful; however, 2 hours after surgery, the patient developed cardiac tamponade, requiring resuscitation and pericardiocentesis. In retrospect, near-infrared spectroscopy (NIRS) showed a gradual decline in cerebral oxygenation (crSO2) in the 30 min prior to the cardiac arrest, while other vital signs were within normal ranges. Our case demonstrates that cerebral NIRS monitoring can serve as an additional clinical marker for early recognition of impending cardiac tamponade.


Melanins and melanogenesis: from pigment cells to human health and technological applications.
During the past decade, melanins and melanogenesis have attracted growing interest for a broad range of biomedical and technological applications. The burst of polydopamine-based multifunctional coatings in materials science is just one example, and the list may be expanded to include melanin thin films for organic electronics and bioelectronics, drug delivery systems, functional nanoparticles and biointerfaces, sunscreens, environmental remediation devices. Despite considerable advances, applied research on melanins and melanogenesis is still far from being mature. A closer intersectoral interaction between research centers is essential to raise the interests and increase the awareness of the biomedical, biomaterials science and hi-tech sectors of the manifold opportunities offered by pigment cells and related metabolic pathways. Starting from a survey of biological roles and functions, the present review aims at providing an interdisciplinary perspective of melanin pigments and related pathway with a view to showing how it is possible to translate current knowledge about physical and chemical properties and control mechanisms into new bioinspired solutions for biomedical, dermocosmetic, and technological applications.


Cigarette smoking, fish consumption, omega-3 fatty acid intake, and associations with age-related macular degeneration: the US Twin Study of Age-Related Macular Degeneration.
To evaluate modifiable risk and protective factors for age-related macular degeneration (AMD) among elderly twins. The US Twin Study of Age-Related Macular Degeneration comprises elderly male twins from the National Academy of Sciences-National Research Council World War II Veteran Twin Registry. To determine genetic and environmental risk factors for AMD, twins were surveyed for a prior diagnosis of AMD and underwent an eye examination, fundus photography, and food frequency and risk factor questionnaires. This environmental component of the study includes 681 twins: 222 twins with AMD (intermediate or late stages) and 459 twins with no maculopathy or early signs. Risk for AMD according to cigarette smoking and dietary fat intake was estimated using logistic regression analyses. Current smokers had a 1.9-fold increased risk (95% confidence interval, 0.99-3.68, P = .06) of AMD while past smokers had about a 1.7-fold increased risk (95% confidence interval, 1.2-2.6, P = .009). Increased intake of fish reduced risk of AMD, particularly for 2 or more servings per week (P trend = .04). Dietary omega-3 fatty intake was inversely associated with AMD (odds ratio, 0.55; 95% confidence interval, 0.32-0.95) comparing the highest vs lowest quartile. Reduction in risk of AMD with higher intake of omega-3 fatty acids was seen primarily among subjects with low levels (below median) of linoleic acid intake, an omega-6 fatty acid (P trend<.001). The attributable risk percentage was 32% for smoking and the preventive fraction was 22% for higher omega-3 intake. This study of twins provides further evidence that cigarette smoking increases risk while fish consumption and omega-3 fatty acid intake reduce risk of AMD.


Constructions of educational meaning in the narratives of four deaf women teachers.
Deaf teachers bring unique perspectives to the teaching of deaf and hard of hearing students, yet their "voices" have been recognized in neither sociological, psychological, nor philosophical accounts of education and deafness. In the present ethnographic study, narrative analysis is used to frame a description of how four deaf women make sense of their lives as teachers as they disclose their beliefs concerning teaching, their deafness, and their connection with the Deaf community.


Delayed-type hypersensitivity to contact allergens in psoriasis. A clinical evaluation.
The possibility for patch testing procedures to detect contact allergy was examined in 85 hospitalized patients with forms of psoriasis. Exclusion criteria were active lesions on the back, the use of strong topical corticosteroids, methotrexate, cyclosporin and UV therapy. After screening, a group of 47 patients with different forms of psoriasis were selected for patch testing. Personal history, including topical treatment, occupation and domestic circumstances, were reasons to extend the standard series of allergens. Tars, nickel sulfate, perfume and balsam of Peru scored high. The overall positive rate was 68%. This is higher than that observed in earlier studies. The unexpected results are discussed in the light of the possible mechanism of action.


Increased vascular response to calcium channel agonist by Dahl S rat kidney.
We examined responses to the calcium channel agonist, BAY-K 8644, of isolated perfused kidneys from Dahl salt-sensitive (DS) and -resistant (DR) rats that had been stabilized on high (HI) and low (LO) NaCl intakes. Mean arterial pressures of DS/HI rats exceeded those of the other three groups. BAY-K 8644 significantly increased the renal vascular resistance (RVR) of DS/HI and DS/LO kidneys, by 38 and 12%, respectively, but did not increase RVR of DR/HI or DR/LO kidneys significantly (6 and 2%, respectively). Increases in RVR and decreases in glomerular filtration rate of DS/HI kidneys exceeded those of DR/HI kidneys. Increases in the RVR of DS/LO kidneys exceeded those of DR/LO kidneys. Experiments utilizing the separate calcium channel agonist and antagonist enantiomers of BAY-K 8644 corroborated these findings, but at lower concentrations. "Chemical sympathectomy" with 6-hydroxydopamine increased the reactivity of kidneys from only high-NaCl animals to BAY-K 8644 without regard to Dahl S or R status. In conclusion, the DS kidney vasculature manifests an increase in responsiveness to this calcium channel agonist, independently of antecedent NaCl loading or high blood pressure. However, a high antecedent salt intake or hypertension enhances vascular responsiveness of the DS kidney to BAY-K 8644.


Stress and drug abuse-related disorders: The promising therapeutic value of neurosteroids focus on pregnenolone-progesterone-allopregnanolone pathway.
The pregnenolone-progesterone-allopregnanolone pathway is receiving increasing attention in research on the role of neurosteroids in pathophysiology, particularly in stress-related and drug use disorders. These disorders involve an allostatic change that may result from deficiencies in allostasis or adaptive responses, and may be downregulated by adjustments in neurotransmission by neurosteroids. The following is an overview of findings that assess how pregnenolone and/or allopregnanolone concentrations are altered in animal models of stress and after consumption of alcohol or cannabis-type drugs, as well as in patients with depression, anxiety, post-traumatic stress disorder or psychosis and/or in those diagnosed with alcohol or cannabis use disorders. Preclinical and clinical evidence shows that pregnenolone and allopregnanolone, operating according to a different or common pharmacological profile involving GABAergic and/or endocannabinoid system, may be relevant biomarkers of psychiatric disorders for therapeutic purposes. Hence, ongoing clinical trials implicate synthetic analogs of pregnenolone or allopregnanolone, and also modulators of neurosteroidogenesis.


[Obesity and low-grade systemic inflammation].
The aim of this review is to deal with the significance of obesity as a promotor of a chronic low-grade inflammatory reaction favouring the development of atherosclerosis and cardiovascular diseases. Adipose tissue synthetizes and releases inflammatory cytokines involved in various atherothrombotic mechanisms and in glucose and lipid metabolism. A local renin-angiotensin system may partially support the obesity related hypertension. Most obese subjects had elevated plasma levels of inflammatory markers which correlate with the degree of obesity and insulin resistance and decrease after weight reduction and exercise. Some evidences suggest that long-chain polyunsaturated fatty acids and thiazolidinediones may be useful in preventing atherosclerosis. Obesity, by itself, has been considered an independent risk factor for cardiovascular diseases. The hypothesis that it is linked to the associated low-grade chronic inflammation is supported by the existence of altered indexes of chronic inflammation also in obese children who are free of other pathological conditions. Further research will be required to determine the pathophysiological meaning of the chronic inflammation associated to obesity.


Yet another function of p53--the switch that determines whether radiation-induced autophagy will be cytoprotective or nonprotective: implications for autophagy inhibition as a therapeutic strategy.
The influence of autophagy inhibition on radiation sensitivity was studied in human breast, head and neck, and non-small cell lung cancer cell lines, in cell lines that were either wild type or mutant/null in p53, and in cells where p53 was inducible or silenced. Whereas ionizing radiation promoted autophagy in all tumor cell lines studied, pharmacological inhibition of autophagy and/or genetic silencing of autophagy genes failed to influence sensitivity to radiation in p53 mutant Hs578t breast tumor cells, HN6 head and neck tumor cells, and H358 non-small cell lung cancer cells. The requirement for functional p53 in the promotion of cytoprotective autophagy by radiation was confirmed by the observation that radiation-induced autophagy was nonprotective in p53 null H1299 cells but was converted to the cytoprotective form with induction of p53. Conversely, whereas p53 wild-type HN30 head and neck cancer cells did show sensitization to radiation upon autophagy inhibition, HN30 cells in which p53 was knocked down using small hairpin RNA failed to be sensitized by pharmacological autophagy inhibition. Taken together, these findings indicate that radiation-induced autophagy can be either cytoprotective or nonprotective, a functional difference related to the presence or absence of function p53. Alternatively, these findings could be interpreted to suggest that whereas radiation can induce autophagy independent of p53 status, inhibition of autophagy promotes enhanced radiation sensitivity through a mechanism that requires functional p53. These observations are likely to have direct implications with respect to clinical efforts to modulate the response of malignancies to radiation through autophagy inhibition.


Psychometric characteristics and race-related measurement invariance of stress and coping measures in adults with HIV/AIDS.
Measurement invariance is the extent to which scales have the same meaning across groups, a condition that is necessary prior to conducting between-group comparisons. As stress and coping research increasingly examines the adjustment efforts of African Americans and Caucasians living with chronic health conditions, it is first necessary to assess the equivalence of existing stress and coping measures for both racial groups. This study examined the psychometric properties and measurement invariance of four measures used frequently in stress and coping research. African Americans (n = 204) and Caucasians (n = 83) completed pre- and post-intervention surveys as part of a randomized clinical trial that tested if telephone-administered psychotherapies could reduce depressive symptoms in persons living with HIV/AIDS. Participants completed the ways of coping checklist (WOCC), the coping self-efficacy scale (CSES), the provision of social relations scale (PSRS), and the geriatric depression scale (GDS). Several WOCC subscales initially evidenced poor internal consistency (when computed using summated composites) that improved when measurement models were applied. The 12-week test-retest reliabilities of PSRS total and subscale scores were notably lower in African Americans than Caucasians. Analyses of race-related measurement invariance showed acceptable invariance for the GDS and the CSES but less certain invariance for the WOCC and PSRS. Stress and coping researchers should examine carefully the psychometric properties of study measures within and between racial groups prior to conducting tests of between-group differences.